Opportunistic Infections Update
Until recently, the incidence of opportunistic infections (OIs) had been steadily decreasing. This is partially a result of the use of effective anti-HIV combination therapies containing a protease inhibitor (sometimes called Highly Active AntiRetroviral Therapy or HAART) and partially a result of a general decline in the nmber of people infected several years ago. Although hard figures have not been presented, many researchers at the recent Conference on Retroviruses and Opportunistic Infections noted that they have recently seen increases in the number of new cases of OIs.
This seems to suggest that some people have already worked their way through all or most of the available therapies and can no longer keep their viral loads low enough or their CD4+ counts high enough to ward off the risk of opportunistic infections. At least in theory, there is no magic to this observation. If anti-HIV regimens are working well enough, and some people are seeing their immune health begin to decline, it is natural to expect an increased risk of opportunistic infections. This re-emphasizes the need to start or re-start preventative medications for opportunistic infections. Listed below are summaries of several studies presented at the conference.
Mycobacterium Avium Complex
Mycobacterium avium complex (MAC) is a serious bacterial infection and is one of the most common OIs in people with advanced HIV disease. A recently completed study for the treatment of MAC shows that the three-drug combination of clarithromycin (Biaxin®) + ethambutol (Myambutol®) + rifabutin (Mycobutin®) is more effective than two-drug regimens of either clarithromycin + ethambutol, or clarithromycin + rifabutin. Compared to people on either regimen, those who received the three-drug regimen had more improvements in symptoms and decreases in the number of MAC organisms (called MAC colony forming units) found in their blood. Additionally, people on the three-drug combination had a survival advantage compared to those receiving either of the two-drug regimens.
Further, participants who received clarithro-mycin + rifabutin were more likely to relapse (develop MAC disease again) and develop resistance to clarithromycin. This is important to know as clarithromycin is widely considered to be the most active drug against MAC. Once resistance sets in a person's ability to combat MAC is greatly diminished. The results from this study suggest that the triple combination of clarithromycin+ethambutol+rifabutin should now be considered the standard of treatment for people with MAC disease.
Two hundred and three people with MAC were enrolled in this study, also known as AIDS Clinical Trials Group Study 223. The doses used in the various combinations were 500mg twice a day of clarithromycin, 15mg/kg/day of ethambutol and 450mg once a day of rifabutin.
Cytomegalovirus (CMV) is a potentially life-threatening virus and is the leading cause of blindness in people with HIV disease. Recent evidence suggests that the incidence of CMV is down. A number of studies are looking at the feasibility of stopping therapy aimed at preventing recurrence of CMV disease (or maintenance therapy). Results so far suggest the need for caution when one thinks about stopping maintenance therapy. They underline the continued importance of CD4+ cell counts as the primary measure for determining one's immediate risk of developing CMV.
One study reported on 17 people who stopped their CMV maintenance therapy after getting an increase in CD4+ cell counts from HAART. All of the participants had CD4+ cell counts over 70 and had healed CMV retinitis, an inflammation of the eye that can cause blindness if left untreated. Despite continuing their HAART regimen, five of the seventeen participants had their CMV retinitis reactivated after being off maintenance therapy for 6-28 months. All volunteers who had CMV reactivation had seen their CD4+ cell counts return to below 50 and typically had higher HIV levels compared to people who did not have reactivation. Also, five of the six people with CMV reactivation had very low levels of the immune system marker that has the ability to combat CMV (called CMV-specific lymphoproliferative responses). No participant who maintained CD4+ cell counts above 100 had CMV reactivation.
This study suggests it may be wise to wait until CD4+ cell counts go above 100 for several months before discontinuing CMV maintenance therapy. Also, people who have a subsequent decline in CD4+ cell counts to below 75 may want to reconsider starting CMV main-tenance therapy before CMV reactivation recurs. In many ways, these findings reflect the general guidelines employed for CMV before the use of highly potent antiviral regimens. Earlier guidelines typically suggested taking CMV prevent medications when the CD4+ count fell below 75.
Pneumocystis carinii Pneumonia
Preventative treatment against Pneumocystis carinii Pneumonia (PCP) is typically recommended for HIV-positive persons with CD4+ cell counts below 200 or for those below 300 while persistent fungal infections (thrush) occur.
Preliminary results from a study indicate that it may be safe for people who have improvements from HAART resulting in sustained CD4+ cell counts above 200 and no persistent infections, such as recurrent oral or vaginal thrush to discontinue PCP preventative therapy. All participants had sustained improvements in health due to HAART, including a CD4+ count over 200 cells and HIV levels below 500 copies HIV RNA for at least three months. Participants were assigned to either continue or discontinue their PCP preventative therapies. After a median follow-up of almost seven months, there have been no cases of PCP recurrences. This suggests that it may be a safe strategy for people with continued improvements due to HAART to consider discontinuing their PCP preventative therapies.
Three hundred and thirty-two people participated in this study, all of whom had previous CD4+ cell counts below 200 or had been previously diagnosed with PCP.
Results from a new study suggest that almost all people with HIV who are given the hepatitis A vaccine (VAQTA) achieve levels of antibody that should be protective against hepatitis A virus. Everybody with CD4+ cell counts above 300 showed antibody titer levels that should be protective against hepatitis A compared to 88% of people with CD4+ cell counts below 300. This study suggests that hepatitis A vaccines can be safely administered to people with HIV.
Other studies have reported that people co-infected with HIV and hepatitis C virus (HCV) experience a more rapid decline and generally worse course of liver disease than people infected only with HCV. People with both HIV and HCV have higher viral loads of both viruses. They have more severe fibrosis (abnormal formation of fibrous liver tissue); are more likely to develop cirrhosis (more severe liver damage resulting in the loss of functioning cells); and have higher rates of mortality compared to people only infected with HCV (and not HIV) or people only infected with HIV (and not HCV). Available therapies to treat HCV are limited to the various brands of interferon-alpha (Intron A®, Roferon A®), consensus interferon (Infergen®) or a combination of Intron A and ribavirin sold in a bundle called Rebetron®.
The strongest and longest lasting results generally come from combination therapy with Intron A interferon with ribavirin. Other brands of interferon combined with ribavirin may work as well or perhaps even better, but the forced bundling of ribavirin with Intron A by the sponsor, Schering-Plough, makes it all but impossible for physicians, patients, or even researchers to explore the possible benefits of other such combinations. Other brands of interferon that could be combined with ribavirin may offer different or lesser side effects, or may offer potential advantages in potency. The marketing practice of Schering-Plough which currently block such research and uses can only be described as self-serving and not in the patients best interests.
A number of other drugs are also understudy for the treatment of HCV. Eventually other combinations are likely to become available, perhaps even following in the footsteps of HIV research which found that three drug combinations were usually the most effective.
One disturbing observation reported in some HCV studies involving people who were HCV- but not HIV-infected. It showed that African Americans appear less likely to respond to interferon-alpha therapy compared to Caucasians. Preliminary results suggest that about 30% of Caucasians respond to interferon-alpha therapy compared to only about 5% of African Americans. Conversely, women and Asians seem to have better responses. Whether this is also true of the more potent combination of interferon and ribavirin is unclear. Even across ethnic lines, the maximum success rate of interferon used alone, about 30%, is not very encouraging. Today, it is more important to determine whether African Americans respond as well other ethnic groups to the combination of interferon plus ribavirin. The reason why African Americans do not have as good a response is not known, although this is not the first disease that there has been different responses to therapy based on race. For instance, many studies have shown that African Americans do not respond as well to approved therapies for treating hypertension. More research needs to be focused in this area so that effective therapy against HCV can be given to everyone.
Some of these studies suggest that it is possible for people to stop their preventative or maintenance therapies after getting improved immune response (usually defined by an increase in CD4+ cell count) from HAART. However, it appears that there is increasing risk for people to develop or have relapses to opportunistic infections after HAART fails and CD4+ cell counts start to decline. The availability of better measures of immune response to specific opportunistic infections would help in predicting who can safely stop preventative or maintenance therapies or who needs to restart them.
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